There is currently an urgent need for compounds with broad-spectrum anti-microbial activity for the preparation of new anti-microbial agents. The increasing incidence of infectious disease caused by microbial pathogens in both communities and hospitals is a worldwide health concern. Severe invasive infections are reported as the main complication in cancer therapies, as well as bone marrow transplantation and major surgeries. Infection is also a major concern for immuno-compromised patients with haematological malignancy and/or AIDS.
Amongst bacterial pathogens, there has recently been a significant increase of multi-drug resistance. For example, strains of Staphylococcus aureus (methicillin-resistant or MRSA) and coagulase-negative Staphylococci (CoNS) have become resistant to the most commonly used antibiotics, such that the only available antibiotics uniformly active against them are the glycopeptides, vancomycin and teicoplanin. S. aureus is one of the leading causes of hospital-acquired bacteremia capable of causing a wide range of diseases ranging from superficial skin infections to potentially fatal illnesses such as bloodstream infection, endocarditis and pneumonia (Diekema et al. Clin. Infect. Dis. 2001, 32:S114-132). Other human pathogens that have begun to develop resistance to multiple antibiotics include Streptococcus pneumoniae (the leading cause of nosocomial infections) and Pseudomonas aeruginosa, Haemophilus influenzae and Moraxella catarrhalis (the most common community-acquired respiratory pathogens; Hoban et al. Clin. Infect. Dis. 2001, 32:S81-93).
Fungal infections are also becoming a major health concern for a number of reasons, including the limited number of anti-fungal agents currently available, the increasing incidence of species resistant to older anti-fungal agents, and the growing population of immuno-compromised patients at risk for opportunistic fungal infections. The most common clinical fungal isolate is Candida albicans (comprising about 19% of all isolates). In one study, nearly 40% of all deaths from hospital-acquired infections were due to fungi (Sternberg, Science, 1994, 266:1632-1634).
Thus, new classes of anti-microbial agents are needed to address both the growing resistance amongst microbes to present therapies and the general lack of efficacy of existing antibiotics against slow-growing organisms.
Heterocyclic compounds, especially heterocyclic azole derivatives, have been shown to have a wide spectrum of biological activities. One class of compounds with interesting biological activities is the imidazoles (derivatives containing a five-membered heterocyclic azole). A variety of biological activities have been reported for imidazole derivatives with different substitution patterns (Lee et al. Nature 1994 327:739-745; Abdel-Meguid et al. Biochemistry, 1994, 33:11671; Heerding et al. Bioorg. Med. Chem. Lett. 2001, 11:2061-2065; Bu et al. Tetrahedron Lett. 1996, 37:7331-7334; Lewis J R. Nat. Prod. Rep. 1999, 16:389-418; Lewis J R. Nat. Prod. Rep. 1998, 15:417-437 and 371-395).
Biological activities have also been reported for aryl-imidazole derivatives, for example, these compounds can act as modulators of multi-drug resistance in cancer cells (Zhang et al. Bioorg. Med. Chem. Lett. 2000, 10:2603-2605), inhibitors of p38 MAP kinase (Adams et al. Bioorg. Med. Chem. Lett. 2001, 11:867-2870, McLay et. al. Bioorg. Med. Chem. 2001, 9:537-554) and of cytokines (U.S. Pat. Nos. 5,656,644; 5,686,455; 5,916,891; 5,945,418; and 6,268,370), and inhibitors of bacterial growth (Antolini et al. Bioorg. Med. Chem. Lett. 1999, 9:1023-1028).
Recent reports have indicated that triaryl-imidazole compounds can act as inhibitors of p38 MAP kinase (for example, see LoGrasso et al. Biochemistry. 1997, 36:10422-10427) and as modulators of multi-drug resistance in cancer cells (Sarshar et al. Bioorg. Med. Chem. Lett. 2000, 10:2599-2601), however, these compounds have found use mainly as colour producing reagents (U.S. Pat. Nos. 4,089,747; 5,024,935; 5,047,318; 5,496,702; 5,514,550; and 5,693,589) and as photopolymerization initiators (U.S. Pat. Nos. 6,117,609 and 6,060,216), generally in dimeric form.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.